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Targeted brain proteomics uncover multiple pathways to Alzheimer's dementia.

ABSTRACT: OBJECTIVE:Previous gene expression analysis identified a network of coexpressed genes that is associated with ?-amyloid neuropathology and cognitive decline in older adults. The current work targeted influential genes in this network with quantitative proteomics to identify potential novel therapeutic targets. METHODS:Data came from 834 community-based older persons who were followed annually, died, and underwent brain autopsy. Uniform structured postmortem evaluations assessed the burden of ?-amyloid and other common age-related neuropathologies. Selected reaction monitoring quantified cortical protein abundance of 12 genes prioritized from a molecular network of aging human brain that is implicated in Alzheimer's dementia. Regression and linear mixed models examined the protein associations with ?-amyloid load and other neuropathological indices as well as cognitive decline over multiple years preceding death. RESULTS:Average age at death was 88.6 years. Overall, 349 participants (41.9%) had Alzheimer's dementia at death. A higher level of PLXNB1 abundance was associated with more ?-amyloid load (p?=?1.0?×?10-7 ) and higher PHFtau tangle density (p?=?2.3?×?10-7 ), and the association of PLXNB1 with cognitive decline is mediated by these known Alzheimer's disease pathologies. On the other hand, higher IGFBP5, HSPB2, and AK4 and lower ITPK1 levels were associated with faster cognitive decline, and, unlike PLXNB1, these associations were not fully explained by common neuropathological indices, suggesting novel mechanisms leading to cognitive decline. INTERPRETATION:Using targeted proteomics, this work identified cortical proteins involved in Alzheimer's dementia and begins to dissect two different molecular pathways: one affecting ?-amyloid deposition and another affecting resilience without a known pathological footprint. Ann Neurol 2018;83:78-88.

SUBMITTER: Yu L

PROVIDER: S-EPMC6119500 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Targeted brain proteomics uncover multiple pathways to Alzheimer's dementia.

Yu Lei L Petyuk Vladislav A VA Gaiteri Chris C Mostafavi Sara S Young-Pearse Tracy T Shah Raj C RC Buchman Aron S AS Schneider Julie A JA Piehowski Paul D PD Sontag Ryan L RL Fillmore Thomas L TL Shi Tujin T Smith Richard D RD De Jager Philip L PL Bennett David A DA

Annals of neurology 20180703 1

<h4>Objective</h4>Previous gene expression analysis identified a network of coexpressed genes that is associated with β-amyloid neuropathology and cognitive decline in older adults. The current work targeted influential genes in this network with quantitative proteomics to identify potential novel therapeutic targets.<h4>Methods</h4>Data came from 834 community-based older persons who were followed annually, died, and underwent brain autopsy. Uniform structured postmortem evaluations assessed th ...[more]

PMID: 29908079

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Project description:Patients who have dementia with Lewy bodies and Alzheimer's disease show early degeneration of the cholinergic nucleus basalis of Meynert. However, how white matter projections between the nucleus basalis of Meynert and the cortex are altered in neurodegenerative disease is unknown. Tractography of white matter pathways originating from the nucleus basalis of Meynert was performed using diffusion-weighted imaging in 46 patients with Alzheimer's disease dementia, 48 with dementia with Lewy bodies, 35 with mild cognitive impairment with Alzheimer's disease, 38 with mild cognitive impairment with Lewy bodies and 71 control participants. Mean diffusivity of the resulting pathways was compared between groups and related to cognition, attention, functional EEG changes and dementia conversion in the mild cognitive impairment groups. We successfully tracked a medial and a lateral pathway from the nucleus basalis of Meynert. Mean diffusivity of the lateral pathway was higher in both dementia and mild cognitive impairment groups than controls (all P < 0.03). In the patient groups, increased mean diffusivity of this pathway was related to more impaired global cognition (β = -0.22, P = 0.06) and worse performance on an attention task (β = 0.30, P = 0.03). In patients with mild cognitive impairment, loss of integrity of both nucleus basalis of Meynert pathways was associated with increased risk of dementia progression [hazard ratio (95% confidence interval), medial pathway: 2.51 (1.24-5.09); lateral pathway: 2.54 (1.24-5.19)]. Nucleus basalis of Meynert volume was reduced in all clinical groups compared to controls (all P < 0.001), but contributed less strongly to cognitive impairment and was not associated with attention or dementia conversion. EEG slowing in the patient groups as assessed by a decrease in dominant frequency was associated with smaller nucleus basalis of Meynert volumes (β = 0.22, P = 0.02) and increased mean diffusivity of the lateral pathway (β = -0.47, P = 0.003). We show that degeneration of the cholinergic nucleus basalis of Meynert in Alzheimer's disease and dementia with Lewy bodies is accompanied by an early reduction in integrity of white matter projections that originate from this structure. This is more strongly associated with cognition and attention than the volume of the nucleus basalis of Meynert itself and might be an early indicator of increased risk of dementia conversion in people with mild cognitive impairment.

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Targeted brain proteomics uncover multiple pathways to Alzheimer's dementia.

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Targeted brain proteomics uncover multiple pathways to Alzheimer's dementia.

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